scholarly journals PENTOXIFYLLINE ENHANCES IN VITRO T-CELL ANTITUMOR RESPONSE IN BREAST CANCER PATIENTS

2021 ◽  
Vol 23 (4) ◽  
pp. 785-790
Author(s):  
M. S. Kuznetsova ◽  
J. A. Shevchenko ◽  
J. N. Khantakova ◽  
A. A. Khristin ◽  
I. A. Obleukhova ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Metastatic Breast Cancer ◽  
Tumor Growth ◽  
Cancer Patients ◽  
Cell Activity ◽  
Metastatic Breast ◽  
Antitumor Response ◽  
Healthy Donors

The NF-κB transcription factor controls the expression of genes responsible for cell cycle, apoptosis, and other immunoregulatory functions. Some nonspecific NF-κB inhibitors were found after discovering the possibility of blocking tumor growth through suppression of NF-κB activity, but their use was complicated by multiple side effects, such as interleukin-1β-related systemic inflammation or non-immunerelated complications, which may be due to inhibition of the p65 NF-κB subunit that plays a central role in organogenesis and inflammation. Inhibition of the c-Rel subunit leads to tumor growth restriction by modulating the T-regulatory cell activity.In 2017, Grinberg-Bleyer and co-authors checked the hypothesis that selective inhibition of the c-Rel subunit can be performed using pentoxifylline and will effectively regulate Treg activity during tumor growth. The authors showed that pentoxphylline, an FDA-approved drug, could indeed induce selective degradation of c-Rel without affecting p65, and suggested that such an effect could be effective in suppressing tumor growth. In this regard, we aimed to investigate in vitro how pentoxifylline affect the functional activity and antitumor cytotoxic potential of T-cells in cancer patients.The objects of the study were peripheral blood mononuclear cells from 25 patients with primary breast cancer (no metastases), 15 patients with metastatic breast cancer, and 25 healthy women without breast pathology. Informed consent was obtained from all donors and patients. The study was approved by the local ethics committee.Here we showed that pentoxifylline treatment in vitro enhances the pro-apoptotic and cytotoxic antitumor response via increasing the expression of TRAIL on T-lymphocytes, mainly in healthy donors and patients with metastatic breast cancer, both on intact T-cells and in response to the cells of the tumor line of human breast carcinoma ZR-75-1. In healthy donors, in the presence of pentoxifylline, a population of highly expressing TRAIL CD4 and CD8 T-cells appears. 

scholarly journals 323 Systemic administration of ladiratuzumab vedotin alone or in combination with pembrolizumab results in significant immune activation in the tumor microenvironment in metastatic breast cancer patients

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A349-A349
Author(s):  
Lajos Pusztai ◽  
Hailing Lu ◽  
Christopher Hale ◽  
Anne Grosse-Wilde ◽  
Jennifer Specht ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Immune Response ◽  
T Cells ◽  
Metastatic Breast Cancer ◽  
Cancer Patients ◽  
Cd8 T Cells ◽  
Immune Activation ◽  
Metastatic Breast ◽  
Breast Cancer Patients

BackgroundLadiratuzumab vedotin (LV) is an investigational antibody-drug conjugate (ADC) composed of a humanized anti-LIV-1 IgG1 conjugated with monomethyl auristatin E (MMAE), a microtubule-disrupting agent. LV targets LIV-1, a protein expressed by various cancers. Along with a cytotoxic effect, LV has been shown to induce immunogenic cell death (ICD) in preclinical studies. LV is currently being investigated as a monotherapy and in combination with pembrolizumab in patients with metastatic breast cancer and other solid tumors. This correlative biomarker study aims to assess the ability of LV to modulate the tumor microenvironment (TME) in breast cancer patients.MethodsIn the SGNLVA-001 trial, metastatic breast cancer patients, predominantly of the triple negative subtype (TNBC), received LV monotherapy (2.0 or 2.5 mg/kg, every 3 weeks [q3w]). In the SGNLVA-002 trial, patients with metastatic TNBC received LV (2.0 or 2.5 mg/kg, q3w) plus pembrolizumab (200 mg, q3w). To investigate the potential effect of LV or LV plus pembrolizumab on the TME, paired pre-treatment and on-treatment tumor biopsies (Cycle [C] 1 Day [D] 5 or C1D15) were collected and analyzed by RNAseq and immunohistochemistry (IHC) staining.ResultsGene expression analysis of paired biopsy TNBC samples (n=59; baseline and C1D5) showed that LV monotherapy treatment significantly induces immune response-related gene expression, MHC, co-stimulatory molecules, and PD-L1. Gene set enrichment analysis (GSEA) demonstrated enrichment of macrophage and tumor inflammation signature genes, supporting the induction of ICD and enhancement of innate immune response. Paired tumor samples from subjects treated with LV plus pembrolizumab (n=16; baseline and C1D15) showed a broader range of gene expression changes on RNAseq compared to LV monotherapy. GSEA evidenced enrichment of genes associated with cytotoxic CD8 T cells, CD4 T helper cells, dendritic cells, and macrophages, further demonstrating the induction of ICD and activation of an innate immune response. Importantly, the combination had a unique adaptive immune response induction signature. IHC analysis confirmed the increased infiltration of macrophages after LV monotherapy. The combination with pembrolizumab resulted in a further increase in macrophages and a prominent influx of CD8 T cells.ConclusionsSystemic administration of LV monotherapy resulted in immune activation in the TME and macrophage infiltration. The combination of LV plus pembrolizumab resulted in a more potent immune activation in the TME and a prominent influx of CD8 T cells in addition to macrophages. Together these results provide a rationale for the continued clinical investigation of LV alone or in combination with pembrolizumab.Trial RegistrationNCT01969643 and NCT03310957Ethics ApprovalThe study protocols for clinical trials represented in this publication were reviewed by the respective IRB/IEC at each study site and approved before trial participants were screened and enrolled.ConsentNot applicable.

In Vitro Interleukin-8 Production by Monocytes Treated with Lithium Chloride from Breast Cancer Patients

2000 ◽  
Vol 86 (2) ◽  
pp. 149-152 ◽  
Author(s):  
Rosaria Alba Merendino ◽  
Adrians Arena ◽  
Sebastiano Gangemi ◽  
Antonella Ruello ◽  
Elena Losi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Cancer Patients ◽  
Lithium Chloride ◽  
Metastatic Breast ◽  
Suppressive Effect ◽  
Interleukin 8 ◽  
Breast Cancer Patients ◽  
Hematopoietic System

Aims and background Since interleukin-8 (IL-8) has a suppressive effect on hematopoiesis, lithium induces leukocytosis and granulocytosis and mononuclear cells are defective in patients affected by neoplastic disease, we analyzed IL-8 production by monocytes obtained from patients with non-metastatic breast cancer (BCaMO) and metastatic breast cancer (BCaM1) and the effect of lithium chloride (LiCI) on these cells. Lithium salt compounds are used to limit the degree and duration of neutropenia in patients receiving chemotherapy for cancer and acute leukemia. Lithium influences the hematopoietic system, which is known to be regulated by numerous cytokines including IL-8. Methods We selected three groups of subjects (15 per group): patients affected by BCaMO, BCaM1 and healthy donors (HD) matched for sex and age. IL-8 release was assessed in supernatants of lipopolysaccharide (LPS) and/or LiCI-treated monocyte cultures. Results Monocytes from BCaM1 released higher IL-8 levels than monocytes from BCaMO (P <0.0001); the IL-8 levels of both groups were significantly higher (P <0.0001) than those of HD. In vitro LiCI treatment reduced IL-8 production by monocytes obtained from all subjects compared to the same cells when untreated or LPS treated. The suppressive effect of LiCI on IL-8 production by monocytes from breast cancer patients was particularly marked in monocytes from BCaMO with respect to those from BCaM1. LPS treatment increased the IL-8 production more in BCaM1 monocytes than in BCaMO monocytes. Moreover, combined LPS/LiCI treatment of monocytes significantly (P <0.0001) downregulated the release of IL-8 compared to treatment with LPS alone. Conclusions Our data demonstrate that monocytes from BCaM1 release larger amounts of IL-8 than monocytes from BCaMO and from HD. Lithium was able to downregulate IL-8 production by monocytes from different subgroups. Further studies are needed to clarify if the improvement of the hematopoietic system in vivo observed following lithium therapy could reside, at least in part, in the ability of lithium to downregulate this chemokine.

Number of Treatment Cycles Influences Development of Cytotoxic T Cells in Metastatic Breast Cancer Patients – A Phase I/II Study

2010 ◽  
Vol 39 (6) ◽  
pp. 570-586 ◽  
Author(s):  
Stephen E. Wright ◽  
Kathleen A. Rewers-Felkins ◽  
Imelda S. Quinlin ◽  
Catherine A. Phillips ◽  
Mary Townsend ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Metastatic Breast Cancer ◽  
Phase I ◽  
Cancer Patients ◽  
Cytotoxic T Cells ◽  
Metastatic Breast ◽  
Breast Cancer Patients ◽  
Number Of Treatment

scholarly journals PD-L1 expression on circulating tumor cells and platelets in patients with metastatic breast cancer

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0260124
Author(s):  
Elizabeth P. Darga ◽  
Emily M. Dolce ◽  
Fang Fang ◽  
Kelley M. Kidwell ◽  
Christina L. Gersch ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Cancer Patients ◽  
Immune Checkpoint ◽  
Whole Blood ◽  
Metastatic Breast ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Breast Cancer Patients ◽  
Healthy Donors

Background Immune checkpoint inhibition is effective in several cancers. Expression of programmed death-ligand 1 (PD-L1) on circulating tumor or immune effector cells could provide insights into selection of patients for immune checkpoint inhibition. Methods Whole blood was collected at serial timepoints from metastatic breast cancer patients and healthy donors for circulating tumor cell (CTC) and platelet PD-L1 analysis with a phycoerythrin-labeled anti-human PD-L1 monoclonal antibody (Biolegend clone 29E.2A3) using the CellSearch® assay. CTC PD-L1 was considered positive if detected on at least 1% of the cells; platelet PD-L1 was considered positive if ≥100 platelets per CellSearch frame expressed PD-L1. Results A total of 207 specimens from 124 metastatic breast cancer patients were collected. 52/124 (42%) samples at timepoint-1 (at or close to time of progressive disease) had ≥5 CTC/7.5ml whole blood. Of those, 21 (40%) had positive CTC PD-L1. In addition, platelet PD-L1 expression was observed in 35/124 (28%) at timepoint-1. Platelet PD-L1 was not detected in more than 70 specimens from 12 healthy donors. Platelet PD-L1 was associated with ≥5 CTC/7.5ml whole blood (p = 0.0002), less likely in patients with higher red blood cell counts (OR = 0.72, p<0.001) and a history of smoking tobacco (OR = 0.76, p<0.001). Platelet PD-L1 staining was not associated with tumor marker status, recent procedures or treatments, platelet-affecting drugs, or CTC PD-L1 expression. Conclusion PD-L1 expression was found in metastatic breast cancer patients on both CTC and platelets in an independent fashion. Inter-patient platelet PD-L1 expression was highly heterogeneous suggesting that it is a biological event associated with cancer in some but not all patients. Taken together, our data suggest that CTC and platelet PD-L1 expression could play a role in predicting which patients should receive immune checkpoint inhibition and as a pharmacodynamics biomarker during treatment.

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